11-Aminoalkyl- and 11-cyclicaminomorphanthridines

ABSTRACT

The compounds are 11-aminoalkylmorphanthridines and 11cyclicaminomorphanthridines which are useful as central nervous system depressants of the tranquilizing type, muscle relaxants and analgetic agents. Representative of the compounds disclosed are 11-(3-dimethylaminopropyl)morphanthridine and 11-(N-methyl-4piperidyl)morphanthridine. The method of preparing the compounds is by the oxidation of the corresponding 5,6dihydromorphanthridine with active manganese dioxide.

United States Patent [1 1 [111 33%,001 Drukker July 8 1975 ll-AMINOALKYL- AND [56] References Cited 11 l-CYCLICAMINOMORPHANTHRIDINES UNITED STATES PATENTS [7 5] Inventor: Alexander E. Drukker, Milwaukee, 3,317,537 5/1967 Drukker 260/239 D Wis.

[73] Assignee: Colgate-Palmolive Company, New Primary Examifer Henry mes York Assistant Exammer-Robert T. Bond Attorney, Agent, or Firm-T. F. Kryshak; M. L. [22] Filed: Nov. 20, 1972 Youngs [21] Appl. No: 307,933

Related U.S. Application Data [57] AESTMW [63] continuatiomimpart of Ser. No. 848,355, Aug. 7, The compounds are 1l-ammoalkylm0rphanthrldmes 1969, Pat 3,699,099, and a continuatiomimpart and ll-cyclicaminomorphanthridines which are useful f 48506, J 22 97 abandoned as central nervous system depressants of the tranquilizing type, muscle relaxants and analgetic agents. Rep- [52] Us. C1 ..260/239 D; 260/247.1 M; resentative 0f the Compounds disclosed are H 260/247.5 R; 260/326.5 CA; 260/326.81; dimethylaminopropyl)morphanthridine and 260/268 TR; 424/244; 424/248; 424/250; methyl-4-piperidyl)morphanthridine. The method of 424/2 7; 424/274; 2 0/293 59 preparing the compounds is by the oxidation of the [51] Int. Cl C07d 41/08 Corresponding y 0 p r n w [58] Field of Search. 260/239 D, 247.1 M, 247.5 R, rive manganese dioxide- 260/326.5 CA, 326.81, 268 TR, 293.59

11% Claims, No Drawings RELATED CASES This application is a continuation in-part of my pending applications Ser. Nos. 848,355 now U.S. Pat. No. 3,699,099 and 48,506, now abandoned, filed Aug.

7, 1969, and June 22, 1970, respectively.

DESCRIPTION OF Til-IE INVENTION The compounds of the present invention may be represented by the following formulae:

in which X and Y are members of the group consisting of hydrogen, halogen such as chloro, bromo and fluoro, an alkyl of l to 4 carbon 'atoms'such as'methyl and ethyl, an alkoxy of l to 3 carbon atoms such as methoxy, ethoxy and propo'xy, a thio-lower alkyl such, as thiomethyl and thioethyl and trifluoromethyl, R, R and R are hydrogen or a lower alkyl of--1 :to 4 carbon atoms, n is 0 to 4 and Am is se'lectedfrom't.

in which R and R; are selected from hydrogen, lower alkyl of l to 4 carbon atoms such as methyl, ethyl or isopropyl and a phenyl-lower alkyl of 7 to '13 carbon atoms such as benzyl, phenethyl or phenyliso'propyl, or

b. a heterocyclicamino group suchlas morpholino, pyrrolidino, piperidino, N-lower alkyl piperazino in which the lower alkyl is 1 to 4'carbon atoms such as N- methyl piperazino, N-phenyl-lower alkyl piperazino in which the lower alkyl is l to 4 carbon atorns such as N- benzyl piperazino and N-(hydroXy-lower alkyl)- piperazino groups in which the lower alkyl is Ho 4 carbon atoms such as 4-(B-hydroxyethyl piperazino), and

is a c yclicamino group such as 3-'piper idyl', 4-pi peridyl, 3-pyrrolidyl, 3-homopiperidyl and 4-homopiperidyl.

The compounds of the present invention may be conveniently prepared from the corresponding 1 laminoalkyl-S,o-dihydromorphanthridines and the 11- cyclicamino -5,o dihydromorphanthrid ines which have the following formulae in w 'ch X, Y, R, R 1R n, Am and -C are as previously defined.

Representative of the compounds which may be employed as starting materials are l 1-( 3-dimethylaminopropyl )-5 ,-dihydromorphanthridine, 2-chloro-1 l-( 3-dimethylaminopropyl)-5 ,6-dihydromorphanthridine, S-chloro-l l-(3-dimethylaminopropyl)-5,6-dihydromorphanthridine, Z-trifluoromethyl-l l-( 3-dimethylaminopropyl )-5 ,6- dihydromorphanthridine, l 1-(3-diethylaminopropyl)-5,o-dihydromorphanthridine, Z-chloro-l l-(3diethylaminopropyl)-5,6-dihydromorphanthridine, 8-chloro-1 1-(3-diethylaminopropyl)-5,6-dihydromorphanthridine, Z-trifluoromethyl-l l-( 3-diethy laminopropyl)-5 ,6-

dihydromorphanthridine, l 1,-(3-methylarninopropyl)-5,6-dihydromorphanthridine, 2-chloro-l l-(3-methylaminopropyl)-5,6-dihydromorphanthridine, S-chloro-l l-(3-methylaminopropyl)-5 ,6-dihydromorphanthridine, 2-trifluoromethyl-l l-(3-methylaminopropyl)-5,6-

dihydromorphanthridine, l l-(N-methyl-N-benzylaminopropyl)-5,6-dihydromorphanthridine, 2-chloro-l 1-(N-methyl-N-benzylaminopropyl)-5 ,6- dihydromorphanthridine, 8-chloro-1 1-(N-methyl-N-benzylaminopropyl)-5 ,6-

dihydromorphanthridine, 2-trifluoromethyl-l l-( N-methyl-N- benzylaminopropyl)-5,6-dihydromorphanthridine, l l-(N-methyl-piperazinopropyl)-5 ,6-dihydromorphanthridine, 2-chloro-1 l-(N-methyl-piperazinopropyl)-5 ,6-dihydromorphanthridine,

5 8-chloro-l l-(N-methyl-piperazinopropyl)-5 ,6-dihydromorphanthridine,

Z-trifluoromethyl-l 1-( N-methyl-piperazinopropyl)- 5 ,6-dihydromorphanthridine,

1 1-[ 3-(4-hydroxyethylpiperazinopropyl) ]-5 ,6-dihydromorphanthridine, I

l l-[ 3-(4-hydroxyethylpiperazinopropyl)]- morphanthridine,

Z-chloro-l l-[ 3-(4-hydroxyethylpiperazinopropyl) morphanthridine,

8-chloro-l 1-[3-(4-hydroxyethylpiperzinopropyl)]- morphanthridine,

Z-trifluoromethyl-l 1-[3-(4- hydroxyethylpiperazinopropyl) ]-morphanthridine,

l l-(N-methyl-4-piperidyl)-morphanthridine, 2-chloro-1 1-(N-methyl-4-piperidyl)- morphanthridine,

8-chloro-l l-( N-methyl-4-piperidyl morphanthridine,

2-trifluoromethyl- 1 l-(N-methyl-4-piperidyl morphanthridine,

1 l-(N-benzyl-4-piperidyl)-morphanthridine, 2-chloro-1 1(N-benzyl-4-piperidyl)- morphanthridine,

8-chloro-1 l-(N-benzyl-4-piperidyl)- morphanthridine,

2-trifluoromethyl-1 1-( N-benZyl-4-piperidyl morphanthridine,

l l-(l\l-methyl-3-piperidyl)-morphanthridine,

2-chloro-l l-(N-methyl-3-piperidyl)- moi-phanthridine,

8-chloro-l 1-(N-methyl-3-piperidyl)- morphanthridine,

Z-trifluoromethyl-l 1-( N-methyl-3-piperidyl morphanthridine,

1 l-(N-ethyl-3-pyrrolidyl)-morphanthridine,

l l-(N-benzyl-3-pyrrolidyl)-morphanthridine, and

l l-(N-methyl-3-homopiperidyl)-morphanthridine.

The compounds of the present invention have been found to possess utility as pharmaceutical and veterinary agents, especially as central nervous system depressants. For example, in mouse behavioral studies the compound 1 1-(3-dimethylaminopropyl) morphanthridine was found in a dose of 10 mg/kg intraperitoneally to cause central nervous system depression. The studies also indicated that the compound had an LD in excess of 100 mg/kg intraperitoneally.

The forementioned compound was also tested for tranquilizing activity in mice which had been isolated to induce an antisocial aggressive behavior. in the tests the compound was administered to the mice in doses of 5 and 20 mg/kg intraperitoneally and found to have an E10 of about 20 mg/kg. The compound was also tested for analgetic activity in mice and was found to be effective against the effects of electrical stimulation in doses of 40 mg/lcg intraperitoneally.

When employed as pharmaceutical agents the compounds are preferably used in the form of acid addition salts. Such acid addition salts may be conveniently prepared by conventional means such as by contacting the compounds with a suitable acid in a mutual solvent and then removing the solvent to obtain the desired salt. Examples of acids which may be used are hydrochloric acid, succinic acid, tartaric acid, benzoic acid or fumaric acid.

Quarternary ammonium salts of the compounds may be formed by conventional techniques employing a suitable alkylating agent such as methyl chloride, methyl iodide or ethyl bromide.

Pharmaceutical dosage forms containing the active ingredients are generally prepared by combining the active ingredient or ingredients with a major amount of one or more suitable pharmaceutical diluents and then forming the resulting mixture into unit dosage forms suitable for oral or parenteral administration.

The unit dosage forms will generally contain from 5 to 250 mg. of the active ingredients. One or more of such units may be administered daily depending upon the patients physical size and the severity of the condition being treated. However, generally the daily dosage will not exceed 150 mg. of the active ingredient per kilogram of the patients body weight.

Representative of a suitable pharmaceutical composition which may be prepared are the following:

TABLETS l l-(3-Dimethylaminopropyl) morphanthridine 2 Methyl cellulose, 400 cps. Lactose Magnesium stearate Starch The powders, other than magnesium stearate, are granulated with water, passed through a No. 16 mesh screen and dried at 50 C. Magnesium stearate is mixed in and 40 mg. tablets are pressed.

The practice of the invention is further illustrated by the following examples:

EXAMPLE 1 l 1-(3-Dimethylaminopropyl)morphanthridine Active manganese dioxide (25 grams) is refluxed with 250 ml. of benzene using a water separator. After 2 hours, 5.3 grams (0.019 mole) of 11-(3- dimethylaminopropy1)-5,6-dihydromorphanthridine in ml. of benzene is added and the suspension stirred and refluxed for 18 hours. The Mn0 is filtered off, rinsed with benzene, and the filtrate concentrated to yield the crude base. Chromatography over silica gel using benzene-methanol (19:1) as eluent followed by benzene-diethylamine (40: 1) affords 1 1-(3- dimethylaminopropyl)morphanthridine.

Anal. Calcd. for C l-ll N C, 81.97; H, 7.97; N, 10.06.

Found: C, 82.24; H, 8.31; N, 10.22.

EXAMPLE 2 The process of Example 1 is repeated employing in place of l 1-(3-dimethylaminopropyl)-5,o-dihydromorphanthridine one of the following:

2-chloro-1 l-(3-dimethylaminopropyl)-5,6-dihydromorphanthridine,

8-chloro-1 1-( 3-dirnethylaminopropyl )-5 ,6-dihydromorphanthridine,

2-trifluoromethyl-l l-(3-dimethylaminopropyl)-5,6-

9 W R R Y X Y CHR (CHR Am c I II in which X and Y are hydrogen, halo, alkoxy of 1 to 3 and R and R are hydrogen, alkyl of l to 4 carbons or carbons, alkyl of l to 4 carbons, thio-lower alkyl or tribenzyl. fluoromethyl, n is to 4, R, R and R are hydrogen or 5. A compound of Formula II of claim 1 in which X, alkyl of 1 to 4 carbon atoms, Am is Y, R, R and R are hydrogen, n is 0, Am is a. N R,,

in which R;, and R are hydrogen, alkyl of l to 4 carbons 0T p y alkyl 0f 7 to 13 carbons and R and R are hydrogen, alyl of 1 to 4 carbons or or benzyl. yq r amlrw rq p Selected from q P o. A compound of Formula 1 of claim 1 m which x,

lino, pyrrolidlno, prperldino, N-lower alkyl pipera- Y, R R d R are hydrogen, n is 0, Am is zino, N-phenyl-lower alkyl piperazino and N- LhyfIlroxy-lower alkyl) -piperazino, and

is a cyclicamino group selected from 3-piperidyl, 4- \R1 piperidyl, 3-pyrrolidyl, 3-homopiperidyl and 4- homopiperidyl and pharmaceutically acceptable acid addition salts thereof,

2. A compound of Formula I of claim 1 in which X and Y are hydrogen or chloro.

and 1R and R are methyl.

7. A compound of Formula I of claim l in which X is hydrogen, Y is chloro, R, R and R are hydrogen, n

3. A compound of Formula I of claim 1 in which X is Am is and Y are hydrogen or chloro, R, R and R are hydrogen, n is 0, Am is R3 R a R and R and R are methyl.

and 3 and 4 are hydrogen, alkyl of 1 t0 4 carbons 8. A compound of Formula II of claim l in lwhich X benzyl. and Y are hydrogen.

A Compound of Formula I of clam 1 Whlch X 9. A compound of Formula II of claim 1 in which X is hydrogen, Y is chloro, R, R and R are hydrogen, n is hydrogen and Y is ch10r0 IS 0, Am 1s 10. A compound of Formula II of claim 1 in which X andxare hydrogen or chloro, /Rn is 3 or 4-piperidyl and R is an alkyl of 1 to 4 carbons. 

1. A COMPOUND SELECTED FROM COMPOUNDS OF THE FORMULAE:
 2. A compound of Formula I of claim 1 in which X and Y are hydrogen or chloro.
 3. A compound of Formula I of claim 1 in which X and Y are hydrogen or chloro, R, R1 and R2 are hydrogen, n is 0, Am is
 4. A compound of Formula I of claim 1 in which X is hydrogen, Y is chloro, R, R1 and R2 are hydrogen, n is 0, Am is
 5. A compound of Formula I of claim 1 in which X, Y, R, R1 and R2 are hydrogen, n is 0, Am is
 6. A compound of Formula I of claim 1 in which X, Y, R, R1 and R2 are hydrogen, n is 0, Am is
 7. A compound of Formula I of claim 1 in which X is hydrogen, Y is chloro, R, R1 and R2 are hydrogen, n is 0, Am is
 8. A compouNd of Formula II of claim 1 in lwhich X and Y are hydrogen.
 9. A compound of Formula II of claim 1 in which X is hydrogen and Y is chloro.
 10. A COMPOUND OF FORMULA II OF CLAIM 1 IN WHICH X AND Y ARE HYDROGEN OR CHLORO, -C NIS 3 OR 4-PIPERIDYL AND R1 IS AN ALKYL OF 1 TO 4 CARBONS. 